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Abstract：
Ewing sarcoma (EWS) is the second most common pediatric bone tumor. The EWS tumor microenvironment is largely recognized as immune-cold, with macrophages being the most abundant immune cells and their presence associated with worse patient prognosis. Expression of CD99 is a hallmark of EWS cells, and its targeting induces inhibition of EWS tumor growth through a poorly understood mechanism. In this study, we analyzed CD99 expression and functions on macrophages and investigated whether the concomitant targeting of CD99 on both tumor and macrophages could explain the inhibitory effect of this approach against EWS. Targeting CD99 on EWS cells downregulated expression of the \"don\'t eat-me\" CD47 molecule but increased levels of the \"eat-me\" phosphatidyl serine and calreticulin molecules on the outer leaflet of the tumor cell membrane, triggering phagocytosis and digestion of EWS cells by macrophages. In addition, CD99 ligation induced reprogramming of undifferentiated M0 macrophages and M2-like macrophages toward the inflammatory M1-like phenotype. These events resulted in the inhibition of EWS tumor growth. Thus, this study reveals what we believe to be a previously unrecognized function of CD99, which engenders a virtuous circle that delivers intrinsic cell death signals to EWS cells, favors tumor cell phagocytosis by macrophages, and promotes the expression of various molecules and cytokines, which are pro-inflammatory and usually associated with tumor regression. This raises the possibility that CD99 may be involved in boosting the antitumor activity of macrophages.
摘要：
尤因肉瘤（EWS）是第二常见的小儿骨肿瘤。EWS肿瘤微环境在很大程度上被认为是免疫冷，巨噬细胞是最丰富的免疫细胞，它们的存在与患者预后较差有关。CD99的表达是EWS细胞的标志，和它的靶向诱导抑制EWS肿瘤生长通过一个知之甚少的机制。在这项研究中,我们分析了CD99在巨噬细胞上的表达和功能,并研究了CD99同时靶向肿瘤和巨噬细胞是否可以解释这种方法对EWS的抑制作用.在EWS细胞上靶向CD99下调了“不要吃我”CD47分子的表达，但在肿瘤细胞膜的外小叶上增加了“吃我”磷脂酰丝氨酸和钙网蛋白分子的水平，触发巨噬细胞吞噬和消化EWS细胞。此外,CD99连接诱导未分化的M0巨噬细胞和M2样巨噬细胞向炎性M1样表型重编程。这些事件导致EWS肿瘤生长的抑制。因此，这项研究揭示了我们认为以前未被识别的CD99的功能，它产生了一个良性循环，将内在的细胞死亡信号传递给EWS细胞，有利于巨噬细胞吞噬肿瘤细胞，并促进各种分子和细胞因子的表达，它们是促炎的，通常与肿瘤消退有关。这增加了CD99可能参与增强巨噬细胞的抗肿瘤活性的可能性。
